Belzutifan plus cabozantinib displays clinical efficacy in treatment-exposed clear cell renal cell carcinoma

Combining the HIF2a inhibitor belzutifan with cabozantinib yields promising results in patients with advanced clear cell renal cell carcinoma (ccRCC). In a cohort of previously treated advanced ccRCC patients, the treatment induced a response in a fifth of patients with 90% of patients having disease control. Also the results with respect to progression-free (PFS) and overall survival (OS) were encouraging, which did not come at the cost of unmanageable toxicity.

Introduction

Up to 90% of patients with clear cell renal cell carcinoma (ccRCC) harbour mutations in the VHL gene, resulting in a defective VHL protein. This loss-of-function induces a state of pseudohypoxia, leading to the activation of HIF-2α which is subsequently involved in the activation of genes associated with angiogenesis (VEGFA and PDGFB), proliferation (CDK), and tumour growth (TGFa). At ASCO GU 2021, results were presented of a phase II study assessing the effect of combining the HIF2a inhibitor belzutifan with cabozantinib in patients with advanced ccRCC. 

The study enrolled 100 advanced or metastatic ccRCC patients who were either treatment-naïve (Cohort 1) or had prior exposure to immunotherapy (Cohort 2) and treated them with the combination of belzutifan (120 mg/day) and cabozantinib (60 mg/day). Patients in cohort 2 were allowed to have received a maximum of 2 prior treatment regimens. The primary endpoint of this study was objective response rate (ORR), with progression-free survival (PFS), time to response (TTR) and safety/tolerability as secondary study objectives. During ASCO GU 2021, interim results for cohort 2 were presented.

Disease control in 90% of patients

The median follow-up of cohort 2 (N= 52) was 8.9 months, with 41 patients still on treatment. The median age of these patients was 63 years, with 46% having had 2 prior lines of therapy. At the time of the analysis, an ORR of 22% was reported entirely consisting of partial responses. An additional 68% of patients experienced disease stabilization for a disease control rate of 90%. Notably, of the stable disease patients 5 (12%) had an unconfirmed partial response. Overall, 88% of patients experienced a reduction in target lesion size. The median TTR was 1.9 months, while the median duration of response was not yet reached. Of note, at the time of data cut-off (15 oct 2020), all confirmed responses were still ongoing. Survival outcomes were positive, with a observed median PFS of 16.8 months and 6- and 12-month PFS rates of 78% and 65%, respectively. OS rates were also encouraging, with 6- and 12-month rates of 95% and 81%.

Any grade treatment-related adverse events (TRAEs) occurred in 98% of patients, with 60% experiencing grade 3 TRAEs. The most common grade 3 TRAEs were anaemia (12%), fatigue (12%) and hand-foot syndrome (2%). Treatment-related hypoxia, an AE of special interest with belzutifan occurred in 2 patients (4%), both being grade 3. No grade 4 or 5 TRAEs were reported and no treatment-related deaths occurred during this study. Twelve percent of patients discontinued belzutifan due to TRAEs, with 15% discontinuing cabozantinib for the same reason.

Conclusion

Belzutifan in combination with cabozantinib offers promising results for treatment-exposed ccRCC patients at this interim analysis, with an ORR of 22% and an unconfirmed partial response in a further 5 patients. Furthermore, the median OS was not reached, with all confirmed responses ongoing at time of data cut-off. The data obtained from this analysis, combined with a manageable safety profile, support the hypothesis of targeting the underlying pathology with dual HIF-2α and VEGFA inhibition.

Reference

Choueiri TK et al., Phase 2 study of the oral hypoxia-induced factor 2α (HIF-2α) inhibitor MK-6482 in combination with cabozantinib in patients with advanced clear cell renal cell carcinoma (ccRCC). Presented at ASCO GU 2021; Abstract 272.